Cyclosporines are cyclic oligopeptides from lower fungi, which were discovered by scientists of Sandoz AG, Basel. Particularly, cyclosporine A or cyclosporine B are used as immunosuppressants, in particular in organ transplantations. Moreover, the cyclosporine derivative "SDZ IMM 125", a hydroxy ethyl derivative of D-serine-8-cyclosporine, is preferred. The application for other diseases, e.g. diabetes and psoriasis and numerous autoimmune diseases (e.g. rheumatoid arthritis, endogenous uveitis, etc.) has also been described.
The most known cyclosporine is cyclosporine A (formula: C.sub.62 H.sub.111 N.sub.11 O.sub.12).
Cyclosporine A is obtained as a white amorphous powder by means of column chromatography over silica gel from fungi, it crystallizes from acetone in white needles having a melting point of 148.degree. to 151.degree. C. In addition to cyclosporine A, numerous other cyclosporines ranging from cyclosporine A to cyclosporine Z are known (R ompps Chemie Lexikon, 9th edition, pages 841 to 843).
Semisynthetic derivatives of cyclosporine are known and can be used according to the invention. These are substances which are very similar to each other in chemical respect, which consist of cyclic polypeptides of 11 partly methylated amino acids. Cyclosporines are soluble in alcohol, ether, acetone and chlorinated hydrocarbons and natural oils (triglycerides of fatty acids).
Cyclosporine A is described and commercially available as a solution for oral administration, which is dissolved in a mixture of alcohol with a vegetable oil (Pharmacopoeia Martindale, 29th edition, US Pharm. XXII, 619).
In addition to oral administration, the intravenous administration of cyclosporine A is in particular also of importance, since, above all, directly after organ transplantations, an oral administration is not possible. Since cyclosporines are insoluble in an aqueous medium, cyclosporine is dissolved in a mixture of alocohol and poly(oxyethylene)-40-castor oil, diluted prior to administration with saline solution or glucose solution and slowly infused for intravenous administration.
A cyclosporine concentrate for injection is described in the United States Pharmacopoeia XXII, 619), which is to be a sterile solution of cyclosporine in a mixture of alcohol with a suited vegetable oil. This form of presentation is not only unsuited for injections, but even lethal, since a critical embolism may immediately occur, if an oil is injected in this form.
Consequently, the intravenously applicable form of cyclosporine A is only commercially available in he form of the aforementioned concentrate with alcohol and poly(oxyethylene)-40-castor oil as Sandimmun.sup.(R) infusion concentrate. The adjuvants alcohol and poly(oxy-ethylene)-40-castor oil used for dissolving cyclosporine A are not only no ideal, but even dangerous adjuvants. Due to the content of alcohol, there is a health risk above all for persons suffering from a liver disease, alcoholics, epileptics, brain-injured persons, pregnant women and children. Poly(oxyethylene)-40-castor oil in injection and infusion solutions can lead to hypersensitivity reactions particularly in persons with susceptibility to allergic diseases or in persons to whom a preparation containing poly(oxyethylene)-40-castor oil has already been administered as an injection or infusion a short time ago, which can manifest themselves as a decrease in blood pressure, defective circulation with blueness of the lips and finger nails, dyspnoea and hot flushes with temporary blushing of the skin. These reactions can differ in terms of time and extent and also lead to life-threatening conditions. Moreover, an increase in the lipids in the blood with pathological shifting of the lipoprotein pattern, an impairment of the flow properties of the blood and of the aggregation ability of the erythrocytes may occur in the case of a long-term administration. (Technical Information of Sandimmun.sup.(R) ; attention in the case of poly(oxyethylene)-40-castor oil in injection and infusion solutions, Deutsche Apothekerzeitung 125, 769 (1985), Pharmakopoeia Martindale, 29th edition (1989), 614 to 619). Poly(oxyethylene)-40-castor oil (e.g. Cremophor.sup.(R) EL) is a non-ionic emulsifier produced by reacting 35 moles of ethylene oxide with 1 mole of castor oil. Cremophor EL is not covered by the natural oils and, as opposed to them, is soluble in water.
Consequently, it is of great importance to have cyclosporine-containing injection solutions or infusion solutions available, which neither contain alcohol nor poly(oxyethylene)-40-castor oil and which, nevertheless, contain cyclosporine in a therapeutically sufficient amount and are also well tolerable and can be administered without the side effects described above.
Although these problems have been known for more than ten years, so far nobody has succeeded in making available a suited injection solution or infusion solution with cyclosporines for intravenous administration despite all efforts.